Solid dosage forms of fenofibrate

ABSTRACT

An improved solid dosage form of fenofibrate which exhibits improved dissolution properties leading to increased bioavailability of fenofibrate. A novel core-shell approach to the composition is provided as well as a process for the preparation of the improved solid dosage forms.

RELATED APPLICATIONS

This application claims priority from Indian Application 1650/CHE/2010filed on Jun. 14, 2010.

FIELD OF THE INVENTION

The present invention relates to a solid dosage form comprisingfenofibrate. The present invention also relates to a process forpreparation of solid dosage form comprising fenofibrate.

BACKGROUND OF THE INVENTION

Fenofibrate is a lipid regulating agent, chemically known as2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethylester and is disclosed in U.S. Pat. No. 4,058,552. Fenofibrate iscurrently marketed in the United States under the tradenames TRICOR®,FENOGLIDE® and TRIGLIDE® in the form of tablets and with the tradenamesANTARA® and LIPOFEN® in the form of capsules.

Bioavailability is the degree to which a drug becomes available to thetarget tissue after administration. Many factors can affectbioavailability including the dosage form and various properties, e.g.,dissolution rate of the drug. Poor bioavailability is a significantproblem encountered in the development of pharmaceutical compositions,particularly those containing an active ingredient that is poorlysoluble in water. Poorly water soluble drugs, those having solubilityless than about 10 mg/ml, tend to be eliminated from thegastrointestinal tract before being absorbed into the circulation.

The solubility of an active pharmaceutical ingredient influences thebioavailability of the drug. Fenofibrate is a poorly soluble drug. Dueto its poor hydrosolubility, fenofibrate poses problem of lowdissolution. It is also poorly absorbed in the digestive tract andconsequently its bioavailability is incomplete and irregular. Clearly,there is a need for improved compositions in which the fenofibrateexhibits better dissolution properties.

There are several prior art references which discloses various attemptsto improve the solubility of fenofibrate.

U.S. Pat. No. 4,800,079 and U.S. Pat. No. 4,961,890 discloses granuleswith controlled release of fenofibrate, each granule comprising an inertcore, a layer based on fenofibrate and a protective layer, wherein theimprovement comprises the layer based on fenofibrate containing thefenofibrate in the form of crystalline microparticles of dimensions notgreater than 30 microns, said microparticles being included in the poresof an inert matrix soluble in water.

U.S. Pat. No. 4,895,726 discloses a composition containing aco-micronized mixture of particles of fenofibrate and a solidsurfactant, wherein the mean particle size of said co-micronized mixtureis less than 15 μm.

U.S. Pat. No. 5,145,684 discloses particles consisting essentially of acrystalline drug substance having a solubility in water of less than 10mg/ml, said drug substance having a non-crosslinked surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than about 400 nm.

U.S. Pat. No. 6,027,747 discloses a solid dispersion comprisingfenofibrate in a hydrophilic polymer and a surfactant prepared byco-precipitation.

U.S. Pat. No. 6,074,670, U.S. Pat. No. 6,596,317 and U.S. Pat. No.7,037,529 discloses fenofibrate composition comprising inerthydrosoluble carrier covered with at least one layer containing afenofibrate active ingredient in a micronized form having a size lessthan 20 μm, a hydrophilic polymer and, optionally, a surfactant andfurther processing them into a suitable dosage form.

U.S. Pat. No. 6,375,986 discloses solid dose nanoparticulate compositioncomprising at least one poorly soluble active agent, at least onepolymeric surface stabilizer adsorbed to the surface of the drug, DOSS,and a pharmaceutically acceptable carrier, as well as any desiredexcipients. The patent further discloses the use of solid dosenanoparticulate composition for the preparation of suitable dosage form.

U.S. Pat. No. 6,696,084 discloses a process for the preparation of smallparticles or microparticles containing fenofibrate and a phospholipidsurface stabilizing substance comprising the steps of: a) mixing at highshear an admixture of fenofibrate and a phospholipid in an aqueouscarrier in the absence of an organic solvent within a temperature rangeat or above the melting point of the fenofibrate to form a heatedsuspension containing the fenofibrate, then b) homogenizing said heatedsuspension in a pressure range and within said temperature range to forma heated homogenate containing the fenofibrate then c) spray drying theheated homogenate to form dried small particles.

U.S. Pat. No. 6,180,138 discloses a process for preparing a dosage formcomprising the steps of premixing the lipid-regulating agent with anexcipient, micronizing the powdered mixture, suspending the micronizedpowdered mixture in a surfactant solution, drying the mixture, wet ordry granulating the mixture, and optionally forming a finished oraldosage form of the resulting formulation.

U.S. Pat. No. 6,368,622 discloses a process for preparing a solidformulation comprising the steps of forming a mixture of thelipid-regulating agent with a solid surfactant, and granulating themixture by melting, mixing, and congealing, then optionally forming afinished dosage form.

U.S. Pat. No. 6,383,517 discloses a process for preparing a solidformulation comprising the steps of dissolving the lipid-regulatingagent in a surfactant solution, premixing an excipient, wet granulatingthe lipid-regulating agent/surfactant solution and the premix, dryingthe resulting mixture, and optionally sizing the dried granules andforming a finished dosage form.

U.S. Pat. No. 6,444,225 discloses a process of making a compositioncomprising a solid dispersion of a disintegrant dispersed infenofibrate, which comprises the steps of melting the fenofibrate,blending the disintegrant into the molten fenofibrate, and solidifyingthe mixture.

U.S. Pat. No. 6,465,011 discloses a solid formulation comprising thelipid-regulating agent dispersed in a hydrophilic, amorphous polymer inwhich said lipid-regulating agent is present as a metastable, amorphousphase.

U.S. Pat. No. 6,531,158 discloses a drug delivery system comprisingmicronized fenofibrate and an inert substrate of suitable particle size,selected from microcrystalline cellulose or lactose, which when orallyadministered as a single 67 mg dose in adults maintains post ingestionblood plasma levels of fenofibric acid of: at least about 100 mg/ml atone hour; at least about 350 mg/ml at two hours; at least about 750mg/ml at four hours; at least about 850 mg/ml at five hours; and atleast about 650 mg/ml at twenty-four hours.

U.S. Pat. No. 6,555,135 discloses a composition comprising acomicronized mixture of fenofibrate, and a solid non-toxic amount of apharmaceutically acceptable excipient having no therapeutic activitythat is not a surfactant.

U.S. Pat. No. 7,101,574 discloses a pharmaceutical composition in theform of granules, wherein each granule comprises a neutral microgranuleon which is a composition comprising: micronized fenofibrate, asurfactant, and a binding cellulose derivative as a solubilizationadjuvant.

U.S. Pat. No. 7,255,877 discloses a method of preparing fenofibratemicroparticles, comprising the steps of: (1) mixing the fenofibrateparticles with (a) a natural or synthetic phospholipid and (b) at leastone non-ionic, anionic, or cationic surfactant to form a mixture, priorto or during a reduction of particle size, and (2) subjecting themixture of step (1) to size reduction by an energy input procedureselected from one or more of sonication, milling, homogenization,microfluidization, or precipitation from solution using antisolvent andsolvent precipitation in the presence of the mixture to producefenofibrate microparticles having a volume-weighted mean particle sizethat is about 50% smaller than particles produced without the presenceof the surfactant using the same energy input procedure.

U.S. Pat. No. 7,276,249 and U.S. Pat. No. 7,320,802 discloses acomposition comprising nanoparticulate fibrate, preferably fenofibrateparticles have an effective average particle size of less than about 500nm and at least one surface stabilizer adsorbed on the surface of thefibrate particles.

U.S. Pat. No. 7,927,627 discloses a nanoparticulate fibrate compositioncomprising: (a) particles of a fibrate or a salt thereof having aneffective average particle size of less than about 2000 nm; and (b)associated with the surface thereof hypromellose, dioctyl sodiumsulfosuccinate, and sodium lauryl sulfate as surface stabilizers;wherein the composition is phospholipid-free.

US 2003/0224059 a drug delivery vehicle comprising at least onepharmaceutical carrier bearing microparticle of a drug, wherein themicroparticles have a mean particle size of about 100 nm to about 10 μm.

US 2004/0115264 discloses fenofibrate tablet, characterized in that itis obtained by compressing a mixture comprising: a) granules containing:1 to 5% of a surfactant; micronized fenofibrate; and at least one solidexcipient selected from starch, cellulose and derivatives thereof, withthe exception of C₁₂ disaccharides, said granules being obtained bygranulating the mixture with the aid of an aqueous solution ofpolyvinylpyrrolidone; b) crosslinked polyvinylpyrrolidone; and c)optionally flow aids or lubricants, the amount of fenofibrate beinggreater than 50% by weight, expressed relative to the weight of thetablet.

US 2005/0112192 and US 2006/0177512 discloses a process for preparing adrug formulation comprising the steps of: dissolving a lipid-regulatingdrug in a solvent free of surfactant to form a drug solution; premixingan excipient to generate an admixture; wet granulating the admixture andthe drug solution to form a granulated drug admixture; and drying thegranulated admixture.

US 2006/0177499 discloses a dry granulation process for preparingcomposition comprising co-micronised mixture of fenofibrate and solidsurfactant.

US 2007/0014853 discloses a dosage form comprising a granulate, whereinthe granulate comprises an active pharmaceutical ingredient having apoor water solubility intimately associated with at least onepharmaceutically acceptable sugar, and wherein when the activepharmaceutical ingredient is fenofibrate, the at least one acceptablesugar is not lactose.

US 2007/0048384 discloses a composition comprising at least one activeagent, at least one pharmaceutically acceptable surfactant and at leastone pharmaceutically acceptable polymer, wherein the active agent isprimarily amorphous fenofibrate.

US 2007/0148245 discloses a process for making a pharmaceuticalcomposition of a drug having low aqueous solubility, the processcomprising (a) fixing the drug in a strong matrix comprising at leastone at least partially amorphous sugar to obtain a sugar-drug matrix;and (b) milling the sugar-drug matrix to obtain a milled sugar-drugmatrix as the pharmaceutical composition, the composition beingoptionally further processed into a pharmaceutical formulation.

US 2008/0050450 discloses a composition comprising fenofibratenanoparticles having an effective average particle size of less than2000 nm, and a particle sequestrant.

US 2008/0095838 discloses a solid pharmaceutical composition for oraladministration; which comprises, within one and the same phase: at leastone solid and micronized lipophilic active principle, at least onesurfactant, at least one cationic polymer insoluble in water at pHgreater than or equal to 5, and at least one organic or inorganic acid.

US 2009/0202649 discloses formulation comprising a dispersion containingfenofibrate and at least one surfactant, optionally combined with one ormore solid organic or inorganic excipients. The patent publication alsodiscloses formulations of fenofibrate prepared by spray drying anemulsion comprising fenofibrate, at least one hydrophilic polymer and atleast one surfactant onto inert substrate cores, or optionallycollecting spray dried solid to obtain a pharmaceutical composition.

US 2010/0151037 discloses a composition comprising nanoparticles offibrate, surfactant, co-surfactant, bulking agent and water and furtherdiscloses a method for the preparation of nanoparticles of a poorlywater soluble drug.

US 2010/0166857 discloses a solid dispersion comprising: a plurality ofcoated particles comprising inert particles with a coating, wherein thecoating comprises fenofibrate dispersed in a hydrophilic polymer, andwherein the inert particles comprise nonpareils; and a plurality ofgranules comprising micronized fenofibrate with at least onepharmaceutically acceptable excipient.

US 2011/0020455 discloses a solid dispersion comprising an activeingredient having a low solubility in water and a powdery porous carrierimpregnated with and supporting the active ingredient, wherein theporous carrier comprises a porous silicon-containing carrier having aheating loss of not more than 4% by weight at a temperature of 950° C.for 2 hours.

EP 0 793 958 B1 discloses a process for the preparation of fenofibratepreparation using fenofibrate, surface-active agents and polyvinylpyrrolidone and optionally one or more further auxiliary or auxiliariesand using mixing and granulation and subsequent drying, characterized inthat firstly fenofibrate particles are mixed with polyvinylpyrrolidoneparticles and crosslinked polyvinylpyrrolidone particles and optionallyfurther auxiliary particles, and the resultant mixture is thengranulated with an aqueous solution of one or more surface-activeagent(s) in a proportion of at least 1.5% by weight, based on the drygranules to be produced and the granules are dried.

WO 00/16749 discloses a method for preparing novel galenic formulationsfor providing fenofibrate with enhanced bioavailability when it isorally absorbed, and consisting in: (a) micronizing fenofibrate; (b)granulating the fenofibrate in the presence of a liquid mediumcomprising a surfactant, water and water-miscible alcohol; and (c)drying the resulting granular material.

WO 01/34119 discloses a solid dispersion formulation comprising apharmaceutical compound, a water soluble carrier, such as polyethyleneglycol (PEG), and a crystallization inhibitor, such aspolyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC).

WO 2004/028506 discloses an immediate release composition comprising aninert hydro-insoluble carrier with at least one layer containingfenofibrate in a micronized form, a hydrophilic polymer and asurfactant; and optionally one or several outer phases or layers.

WO 2008/016260 discloses solid dispersion comprising an amorphousfenofibrate dispersed in a water-soluble polymer.

WO 2008/075320 discloses a process for preparing a compositioncomprising fenofibrate, wherein the process comprises the steps of: (i)preparing a solution comprising fenofibrate, a surfactant and ahydrophilic polymer, (ii) homogenizing the solution of step (i) with oneor more solvents, (iii) spraying the homogenized solution of step (ii)over one or more inert carriers, (iv) drying the granules of step (iii)and blending with one or more pharmaceutically acceptable excipients,(v) compressing the mixture of step (iv) into tablets or filling intocapsules.

WO 2008/104846 discloses composition comprising unmicronized fenofibrateor a salt thereof in admixture with one or more wetting agents and oneor more pharmaceutically acceptable excipients, wherein the admixture isnot co-micronized before processing.

WO 2008/104852 discloses a composition comprising fenofibrate adsorbedon a pharmaceutically acceptable adsorbent optionally, along with one ormore pharmaceutically acceptable excipients.

WO 2008/110534 discloses a process for the preparation of apharmaceutical composition containing poorly soluble drug comprising thesteps of: a) dissolving the drug, or a pharmaceutically acceptable saltthereof, and at least one polymer in a suitable solvent, to form asolution; b) spraying the solution onto inert pellets; and c) drying theinert pellets to remove the solvent.

WO 2009/016608 discloses composition comprising non-micronisedfenofibrate and one or more pharmaceutically acceptable vehiclescomprising one or more of polyethylene glycol or derivatives thereof,poloxamer, Cremophore RH 40 and vitamin E. The patent publicationfurther discloses composition comprising non-micronized fenofibrate andcyclodextrin.

WO 2010/033179 discloses granule for a pharmaceutical composition,comprising a core, which comprises at least one active pharmaceuticalingredient intimately associated with at least one hydrophilic polymer,wherein the active pharmaceutical ingredient has a solubility in waterof less than about 1 mg/ml.

WO 2010/075065 discloses a method of making microparticles comprising:(a) dissolving, melting, or suspending at least one water-insolubleactive agent in at least one fatty acid or conjugated fatty acid,surfactant, hydrophilic polymer, or combinations thereof to form amixture, and (b) mixing the mixture of step (a) with a hydrophilic orlipophilic carrier to form microparticles.

WO 2010/081623 discloses an aqueous suspension comprising crystallinefenofibrate or fenofibric acid having an average particle size of D(50)less than 250 nm, cellulose derivative, solubilizing adjuvant and asurfactant.

WO 2010/115886 discloses an adsorbate comprising an activepharmaceutical ingredient (API) being practically insoluble in waterassociated with a particulate and/or porous carrier, wherein theadsorbate is prepared by using a non-polar solvent or a mixture ofnon-polar solvents, and wherein essentially no API is in the form ofprecipitates, particles or crystals.

WO 2010/146606 discloses a stable nanodispersion comprisingnanoparticles having a mean size less than 300 nm dispersed in a vehiclecomprising a water miscible solvent and water, said nanoparticlescomprising one or more drugs having a polymer and a surfactantcomprising a mixture of fatty acids or its salts and sterol or itsderivatives or its salts.

IN 770/MUM/2007 discloses an immediate release composition comprising aninert core with at least one layer containing fenofibrate innon-micronized form in admixture with pharmaceutically acceptableexcipients and optionally one or more layers.

IN 599/MUM/2008 discloses a composition comprising micronizedfenofibrate, one or more surfactants other than dioctylsulfosuccinatealong with pharmaceutically acceptable excipients.

IN 1384/MUM/2008 discloses a formulation of fenofibrate with enhancedoral bioavailability, simplicity of design and manufacture and absenceof food effect. The formulation comprises fenofibrate dissolved in alipophilic surfactant, with a hydrophilic surfactant optionally added.

IN 1820/DEL/2009 discloses a fenofibrate composition in the form ofcapsules or tablets, comprising fenofibrate, surfactant, hydrophilicpolymer and anti-foaming agents.

IN 1888/CHE/2009 discloses a pharmaceutical composition comprising ahigh drug load of fenofibrate, wherein the fenofibrate is present inmore than 70% by weight of total composition and further discloses aprocess for preparing fenofibrate composition using extrusion process.

The above prior art references disclose various approaches to improvethe solubility as well as bioavailability of fenofibrate. Still, thereexists a need for improved formulations in which the fenofibrateexhibits better dissolution properties. The inventors of the presentinvention have developed a solid dosage form comprising fenofibratewhich increases the rate of dissolution of fenofibrate as well as itsbioavailability.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a solid dosageform comprising fenofibrate and one or more pharmaceutically acceptableexcipients.

Another objective of the present invention is to provide a process forthe preparation of solid dosage form comprising fenofibrate havingbetter dissolution properties, content uniformity and equivalentbioavailability w.r.t commercialized fenofibrate dosage form.

SUMMARY OF THE INVENTION

The present invention relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate        and one or more pharmaceutically acceptable excipients, and    -   c) optionally a film coating.

The present invention further relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate,        hydrophilic polymer/s, a hydrophilic carrier, optionally one or        more surfactants and one or more pharmaceutically acceptable        excipients, and    -   c) optionally a film coating.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of

-   -   a) preparing a tablet core,    -   b) preparing dispersion of fenofibrate in a suitable solvent,    -   c) coating the tablet core with fenofibrate dispersion, and    -   d) optionally film coating the coated tablet.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a solid dosage form comprisingfenofibrate and one or more pharmaceutically acceptable excipients.

The present invention relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate        and one or more pharmaceutically acceptable excipients, and    -   c) optionally a film coating.

The present invention further relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate,        hydrophilic polymer and one or more pharmaceutically acceptable        excipients, and    -   c) optionally a film coating.

The present invention further relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate,        hydrophilic polymer, a hydrophilic carrier, optionally one or        more surfactants and one or more pharmaceutically acceptable        excipients, and    -   c) optionally a film coating.

The present invention further relates to a solid dosage form comprising:

-   -   a) tablet core comprising one or more pharmaceutically        acceptable excipients,    -   b) a layer surrounding the tablet core comprising fenofibrate,        hydrophilic polymer, a hydrophilic carrier, surfactants and one        or more pharmaceutically acceptable excipients, and    -   c) a film coating.

“Tablet core” according to the present invention may be an inert tabletcore comprising one or more pharmaceutically acceptable excipients. Thetablet core may further contain fenofibrate along with one or morepharmaceutically acceptable excipients.

“Fenofibrate” according to the present invention includes, but notlimited to, fenofibrate free base, its pharmaceutical acceptable salts,esters, ethers, solvates, hydrates, polymorphs and the like. Fenofibratemay be used in the range of 1-70% by weight of the composition.

“Pharmaceutically acceptable excipient/s” are the components added topharmaceutical formulation to facilitate manufacture, enhance stability,control release, enhance product characteristics, enhancebioavailability, enhance patient acceptability, etc. Pharmaceuticallyacceptable excipients includes, but not limited to, diluents/fillers,binders, disintegrants, sugars, lubricants, glidants, compression aids,colors, sweeteners, preservatives, surfactants, phospholipids,suspending agents, dispersing agents, film formers, flavors, printinginks, etc.

Binders hold the ingredients in the composition together. Exemplarybinders include, but not limited to, cellulose and its derivativesincluding, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose and hydroxyethyl cellulose,carboxymethyl cellulose; starch and its derivatives; hydrocolloids;sugars; polyvinyl pyrrolidone and combinations comprising one or more ofthe foregoing binders. The binder may be used in the range of 1-15% byweight of the composition.

Diluents increase the bulk of the composition. Diluents according to thepresent invention include, but not limited to, sugars such as lactose,sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol,lactitol; Starlac® (co-processed mixture of Starch and lactose),Microcelac® (co-processed mixture of microcrystalline cellulose andlactose), starch, modified starches, pregelatinized starch, dibasiccalcium phosphate, tribasic calcium phosphate, powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose andthe like or combinations thereof. The diluent may be used in the rangeof 5-80% by weight of the composition.

Disintegrants according to the present invention include, but notlimited to, water swellable substances, for example, cellulose and itsderivatives including low-substituted hydroxypropyl cellulose;cross-linked polyvinylpyrrolidone; cross-linked sodiumcarboxymethylcellulose, sodium carboxy methylcellulose, microcrystallinecellulose; sodium starch glycolate; ion-exchange resins; starch andmodified starches including pregelatinized starch; formalin-casein; andcombinations comprising one or more of the foregoing water swellablesubstances. The disintegrant may be used in the range of 1-20% by weightof the composition.

Lubricants and glidants aids in the processing of powder materials.Exemplary lubricants include, but not limited to, calcium stearate,glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol,sodium stearyl fumarate, stearic acid, talc, vegetable oil, zincstearate, and combinations comprising one or more of the foregoinglubricants. Exemplary glidants include, but not limited to, talc,silicon dioxide, cornstarch and the like. The lubricant may be used inthe range of 0.1-5% by weight of the composition.

Surfactants are compounds which are capable of improving the wetting ofthe drug and/or enhancing the dissolution. The surfactants can beselected from hydrophilic surfactants or lipophilic surfactants ormixtures thereof. The surfactants can be anionic, nonionic, cationic,and zwitterionic surfactants. Surfactants according to the presentinvention include, but not limited to, polyoxyethylene alkylaryl etherssuch as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether; polyethylene glycol fatty acid esterssuch as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate;polyoxyethylene sorbitan fatty acid ester such as polysorbate 40,polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such assorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate,sorbitan trioleate, polyoxyethylene castor oil derivates such aspolyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium laurylsulphate, monooleate, monolaurate, monopalmitate, monostearate, sodiumdioctyl sulfosuccinate (DOSS), lecithin, stearylic alcohol,cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, andthe like or combinations thereof. The surfactant may be used in therange of 0.0001-10% by weight of the composition.

Phospholipids according to the present invention include, but notlimited to, phosphatidylcholine, phosphatidylethanolamine,phosphatidylserine, phosphatidylinositol, phosphatidylglycerol,phosphatidic acid, lysophospholipids, sphingomyelin, egg or soybeanphospholipid, lecithin or combination thereof. The phospholipid may beused in the range of 0-5% by weight of the composition.

The expression “hydrophilic polymer” in the invention should be taken tomean any high molecular weight substance (greater, for example, than300) having sufficient affinity towards water to dissolve therein or toform a gel. Examples of such polymers include, but not limited to,polyvinylpyrrolidone, copovidone, poly(vinyl alcohol), hydroxypropylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl methylcellulose, gelatin and the like or combinationsthereof. The hydrophilic carrier may be used in the range of 0.1-20% byweight of the composition.

“Hydrophilic carrier” according to the present invention means, but notlimited to, any excipient, generally hydrophilic, pharmaceuticallyinert, crystalline or amorphous. Examples of such excipients arederivatives of sugars, such as lactose, saccharose, sucrose, mannitol,sorbitol, cellulose and its derivatives, inorganic salts, starch orhydrolyzed starch (maltodextrin), or the like and mixtures thereof. Thehydrophilic carrier may be used in the range of 5-80% by weight of thecomposition.

Suitable sugars according to the present invention include, but notlimited to, one or more of sucrose, glucose, fructose, galactose,maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose,sorbitol, mannitol, xylitol, lactitol and the like or combinationsthereof.

The tablet core according to the present invention may be prepared byany method known in the art such as wet granulation, dry granulation ordirect compression of the pharmaceutically acceptable excipients.Preferably the tablet core is prepared by direct compression.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) preparing a tablet core,    -   b) preparing dispersion of fenofibrate in a suitable solvent,    -   c) coating the tablet core with fenofibrate dispersion, and    -   d) optionally film coating the coated tablet.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) preparing a tablet core,    -   b) preparing dispersion of fenofibrate along with one or more        pharmaceutically acceptable excipients in a suitable solvent,    -   c) coating the tablets with fenofibrate dispersion, and    -   d) filling the tablets in the hard gelatin capsules.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) preparing a tablet core,    -   b) preparing dispersion of fenofibrate along with one or more        pharmaceutically acceptable excipients in a suitable solvent,    -   c) coating the tablets with fenofibrate dispersion, and    -   d) optionally film coating the coated tablet.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) blending one or more pharmaceutically acceptable excipients,    -   b) compressing the blend of step (a) into a tablet,    -   c) dispersing fenofibrate and hydrophilic polymer in a suitable        solvent,    -   d) coating the tablets of step (b) with fenofibrate dispersion        of step (c), and    -   e) optionally film coating the coated tablet

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) blending one or more pharmaceutically acceptable excipients,    -   b) compressing the blend of step (a) into a tablet,    -   c) dispersing fenofibrate, hydrophilic polymer and a hydrophilic        carrier in a suitable solvent,    -   d) coating the tablets of step (b) with fenofibrate dispersion        of step (c), and    -   e) optionally film coating the coated tablet.

The present invention further relates to a solid dosage form comprisingfenofibrate prepared by the process comprising the steps of:

-   -   a) blending one or more pharmaceutically acceptable excipients,    -   b) compressing the blend of step (a) into tablet,    -   c) dispersing fenofibrate and hydrophilic polymer in a suitable        solvent,    -   d) milling the fenofibrate dispersion,    -   e) dissolving sugar in the dispersion of step (d),    -   f) coating the tablets of step (b) with fenofibrate dispersion        of step (e), and    -   g) optionally film coating the coated tablet.

Dosage form according to the present invention can be selected from thegroup comprising tablets, capsules, minitablets or the like orcombinations thereof.

“Suitable solvent” according to the present invention can be any solventwherein the drug can be either dissolved or dispersed such as isopropylalcohol, ethanol, water, acetone, methylene chloride and the like ormixtures thereof.

“Dispersion” according to the present invention can be microdispersionor nanodispersion. The dispersion can be prepared and milled by methodsknown in the art.

Film coating composition includes one or more polymeric carriers alongwith one or more pharmaceutically acceptable excipients such asplasticisers, opacifier, anti-sticking agent, colorants, sugars, poreforming agent, surfactants and the like. More particularly the filmcoating is Opadry.

Suitable film coating polymers according to the present inventioninclude, but not limited to, ethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide and the likeor combinations thereof.

Suitable plasticizers according to the present invention include, butnot limited to, polyethylene glycol, acetyl triethyl citrate, acetyltributyl citrate, triethyl citrate, acetylated monoglycerides, glycerol,triacetin, propylene glycol, dibutyl phthalate, diethyl phthalate,isopropyl phthalate, dimethyl phthalate, dactyl phthalate, dibutylsebacate, dimethyl sebacate, castor oil, glycerol monostearate,fractionated coconut oil and the like or combinations thereof.

Suitable opacifiers according to the present invention include, but notlimited to, water insoluble pigments comprising titanium dioxide,calcium carbonate, calcium sulfate, magnesium oxide, magnesiumcarbonate, aluminum silicate, aluminum hydroxide, talc, iron oxide andthe like or combinations thereof.

Suitable colorants include water soluble dyes, water insoluble pigmentsand natural colorants.

Suitable anti-sticking agents used according to the present inventionare selected from talc, magnesium stearate and the like or a mixturethereof.

In another embodiment of the present invention, the weight of the tabletcore may be in the range of 50 mg to about 1000 mg.

In another embodiment, the particle size of fenofibrate is in the rangeof about 10 nm to about 200 microns, preferably in the range of about100 nm to about 100 microns and more preferably in the range of about100 nm to about 1 microns.

In yet another embodiment, the amount of fenofibrate used may be in therange of about 10 to about 300 mg.

In another preferred embodiment of the present invention, the soliddosage form comprises:

-   -   a) tablet core comprising 30-50% w/w of lactose, 1-20% w/w of        crospovidone, 30-50% w/w of silicified microcrystalline        cellulose, 0.0001-10% w/w of sodium lauryl sulphate and 0.1-5%        w/w of magnesium stearate,    -   b) a layer surrounding the tablet core comprising 1-70% w/w of        fenofibrate, 1-20% w/w of hydroxypropyl methylcellulose, 0-5%        w/w of lecithin and 5-30% w/w of sucrose, and,    -   c) film coating over the coated tablet,        wherein the % w/w is based on total weight of the dosage form.

In another preferred embodiment, the solid dosage form comprisingfenofibrate is prepared by a process comprising the steps of:

-   -   a) blending lactose, sodium lauryl sulphate, crospovidone and        silicified microcrystalline cellulose,    -   b) lubricating the blend of step (a) with magnesium stearate,    -   c) compressing the blend of step (b) into tablet,    -   d) dispersing fenofibrate and hydroxypropyl methylcellulose in        purified water and stirring to get uniform dispersion,    -   e) milling the fenofibrate dispersion to get fenofibrate having        an average particle size above 600 nm,    -   f) dissolving sucrose and/or lecithin in the dispersion of step        (e),    -   g) coating the tablets of step (c) with fenofibrate dispersion        of step (f), and    -   h) applying a film coating over the coated tablets of step (g).

The following examples further exemplify the invention and are notintended to limit the scope of the invention. It is obvious to thoseskilled in the art to find out the composition for other dosage formsand substitute the equivalent excipients as described in thisspecification or with the one known to the industry.

Example 1

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 258.95 2 Sodiumlauryl sulfate 10.57 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 14.5 8 Sucrose 145 9Purified water q.s Drug loaded tablet weight 739.5 Film coating 10Opadry 15 11 Purified water q.s Film coated tablet weight 754.5

The processing steps involved in manufacturing fenofibrate tablets aregiven below:

-   -   i) lactose, sodium lauryl sulphate, crospovidone and silicified        microcrystalline cellulose were sifted separately and blended,    -   ii) the blend of step (i) was lubricated with magnesium stearate        and    -   iii) the lubricated blend of step (ii) was compressed into        tablets,    -   iv) fenofibrate and hydroxypropyl methylcellulose were dispersed        in water and stirred to get a uniform dispersion,    -   v) the dispersion of step (iv) was nanonized to get fenofibrate        having an average particle size above 600 nm,    -   vi) sucrose was added to the nanodispersion of step (v),    -   vii) the tablets prepared in step (iii) were coated with        nanodispersion of step (vi) and dried, and    -   viii) the coated tablets obtained in step (vii) were coated with        Opadry coating.

Example 2

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 229.39 2 Sodiumlauryl sulfate 40.00 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 14.5 8 Sucrose 145 9Purified water q.s Drug loaded tablet weight 739.5 Film coating 10Opadry 15 11 Purified water q.s Film coated tablet weight 754.5

Example 3

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 223.10 2 Sodiumlauryl sulfate 40.00 3 Crospovidone 20.00 4 Silicified microcrystallinecellulose 151.00 5 Magnesium stearate 0.90 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 14.5 8 Sucrose 145 9Purified water q.s Drug loaded tablet weight 739.5 Film coating 10Opadry 15 11 Purified water q.s Film coated tablet weight 754.5

Example 4

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 258.82 2 Sodiumlauryl sulphate 10.57 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145.00 7 Hydroxypropyl methylcellulose 14.50 8 Sucrose145.00 9 Lecithin 1.00 10 Purified water q s Drug loaded tablet weight740.5 Film coating 11 Instacoat 15.50 12 Purified water q s Film coatedtablet weight 756.00

Example 5

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 258.85 2 Sodiumlauryl sulfate 10.57 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 29 8 Sucrose 141.81 9Microcrystalline cellulose 3.19 10 Purified water q.s Drug loaded tabletweight 754 Film coating 11 Opadry 20 12 Purified water q.s Film coatedtablet weight 774

Example 6

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 258.85 2 Sodiumlauryl sulfate 10.57 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 29 8 Sucrose 135.43 9Microcrystalline cellulose 3.19 10 Crospovidone 6.38 11 Purified waterq.s Drug loaded tablet weight 754 Film coating 12 Opadry 20 13 Purifiedwater q.s Film coated tablet weight 774

Example 7

S. No Ingredients mg/tablet Inert Tablet Core 1 Lactose 258.85 2 Sodiumlauryl sulfate 10.57 3 Crospovidone 13.05 4 Silicified microcrystallinecellulose 151.65 5 Magnesium stearate 0.91 Drug nano-dispersion coating6 Fenofibrate 145 7 Hydroxypropyl methylcellulose 29 8 Sucrose 100.34 9Microcrystalline cellulose 31.9 10 Crospovidone 12.76 11 Purified waterq.s Drug loaded tablet weight 754 Film coating 12 Opadry 20 13 Purifiedwater q.s Film coated tablet weight 774

The compositions given in Examples 2 to 7 were prepared using thesimilar procedure described in Example 1.

Table 1 given below shows the comparative dissolution profile offenofibrate tablets according to the present invention (Examples 1-3)and Tricor® Tablets carried out in 1000 ml medium (water+0.05M sodiumlauryl sulphate) using Apparatus USP II (Paddle), at 50 rpm speed.

TABLE 1 % Drug released Time in min Example-1 Example-2 Example-3Tricor ® 145 mg 10 85 81 76 92 30 93 95 97 96 45 94 96 98 96 60 96 96 9896

1. A solid dosage form comprising: a) tablet core comprising one or morepharmaceutically acceptable excipients, b) a layer surrounding thetablet core comprising fenofibrate and one or more pharmaceuticallyacceptable excipients, and c) optionally a film coating.
 2. The soliddosage form according to claim 1, wherein the layer further compriseshydrophilic polymer, hydrophilic carrier or the combinations thereof. 3.The solid dosage form according to claim 2, wherein the hydrophilicpolymer is hydroxypropyl methyl cellulose and hydrophilic carrier issucrose.
 4. The solid dosage form according to claim 1, wherein thepharmaceutically acceptable excipient is selected from the groupconsisting of diluents/fillers, binders, disintegrants, lubricants,glidants, surfactants, phospholipids and film formers.
 5. The soliddosage form according to claim 4, wherein the diluent can be selectedfrom group consisting of lactose, sucrose, powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose orcombinations thereof.
 6. The solid dosage form according to claim 4,wherein the disintegrant is selected from group consisting ofcross-linked polyvinylpyrrolidone; cross-linked sodiumcarboxymethylcellulose, sodium starch glycolate or combinations thereof.7. The solid dosage form according to claim 4, wherein the surfactant isselected from group consisting of sodium lauryl sulphate, lecithin,sodium dioctyl sulfosuccinate or combinations thereof.
 8. The soliddosage form according to claim 4, wherein the binder is selected fromthe group consisting of hydroxypropyl methylcellulose, sugars; polyvinylpyrrolidone and combinations thereof.
 9. A solid dosage form comprisingfenofibrate prepared by the process comprising the steps of: a)preparing a tablet core, b) preparing dispersion of fenofibrate in asuitable solvent, c) coating the tablet core with fenofibratedispersion, and d) optionally film coating the coated tablet.
 10. Asolid dosage form comprising: a) tablet core comprising 30-50% w/w oflactose, 1-20% w/w of crospovidone, 30-50% w/w of silicifiedmicrocrystalline cellulose, 0.0001-10% w/w of sodium lauryl sulphate and0.1-5% w/w of magnesium stearate, b) a layer surrounding the tablet corecomprising 1-70% w/w of fenofibrate, 1-20% w/w of hydroxypropylmethylcellulose, 0-5% w/w of lecithin and 5-30% w/w of sucrose, and, c)film coating over the coated tablet, wherein the % w/w is based on totalweight of the dosage form.